Stabilized efinaconazole compositions

ABSTRACT

The present invention provides compositions containing efinaconazole, butylated hydroxytoluene, a salt of ethylenediaminetetraacetic acid, and optional citric acid. The compositions exhibit stable color profiles and are useful in the treatment of fungal infections.

CROSS REFERENCES TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 14/505,379, filed on Oct. 2, 2014, which claims priority toU.S. Provisional Patent Application No. 61/886,569, filed on Oct. 3,2013, and U.S. Provisional Patent Application No. 61/922,867, filed onJan. 1, 2014, which applications are incorporated herein by reference intheir entirety.

BACKGROUND OF THE INVENTION

Triazole anti-fungal compounds, such as ketoconazole, itraconazole, andfluconazole are known and have been the subject of scientific study,pharmaceutical development, and medical use. Although compounds in thisclass often exhibit antifungal activity, they differ in terms ofefficacy and usefulness in different types of pharmaceuticalformulations and treatments. Efinaconazole (CAS registry number164650-44-6) is a triazole that has demonstrated activity in thetreatment of onychomycosis. Formulations useful for the topical deliveryof efinaconazole in the treatment of onychomycosis and other triazoleantifungal drugs have been described in, e.g., U.S. Pat. No. 8,486,978.Some formulations containing triazole active ingredients exhibit varyingdegrees of instability during storage. Certain formulations are known todiscolor within storage periods as short as one or two days, resultingin composition colors ranging from yellow to deep red or brown. Suchdiscoloration can discourage the prescribed use of the compositions bypatients who are reluctant to self-administer the discoloredcompositions. Stabilized formulations of triazoles such as efinaconazoleare therefore needed. The present invention addresses this need.

SUMMARY OF THE INVENTION

In a first aspect, the invention provides a liquid or semisolidcomposition containing about 0.5% to about 15% efinaconazole by weight,butylated hydroxytoluene (BHT), and a salt of ethylenediaminetetraaceticacid (EDTA). The amounts of BHT and the salt of EDTA are sufficient toensure the composition is: (i) colorless upon initial formulation, and(ii) colorless or pale yellow after storage for at least three weeks ata temperature of at least about 40° C. In some embodiments, thecomposition is colorless or pale yellow after storage for one month at atemperature of about 65° C.

In some embodiments, the amount of efinaconazole is in the range ofabout 8% (w/w) to about 12% (w/w). In some embodiments, the amount ofefinaconazole is about 10% (w/w). In some embodiments, the amount ofefinaconazole is in the range of about 0.5% (w/w) to about 5% (w/w). Insome embodiments, the amount of efinaconazole is about 2% (w/w).

In some embodiments, the amount of BHT is in the range of about 0.01%(w/w) to about 2% (w/w).

In some embodiments, the amount of EDTA or EDTA salt is in the range ofabout 0.0001% (w/w) to about 1.5% (w/w). In some embodiments, the amountof EDTA or EDTA salt is in the range of about 0.0001% (w/w) to about0.0005% (w/w). In some embodiments, the composition is formulated as asolution. In some embodiments, the amount of EDTA or EDTA salt is about0.00025% (w/w) and the amount of BHT is about 0.1% (w/w)

In some embodiments, the amount of EDTA or EDTA salt is in the range ofabout 0.01% (w/w) to about 1% (w/w). In some embodiments, thecomposition is formulated as a gel. In some embodiments, the amount ofEDTA or EDTA salt is about 0.1% (w/w) and the amount of BHT is about0.1% (w/w).

In some embodiments, the composition further comprises from about 0.01%citric acid (w/w) to about 1% citric acid (w/w). In some embodiments,the composition comprises from about 0.05% citric acid (w/w) to about0.25% citric acid (w/w). In some embodiments, the composition comprisesfrom about 0.075% citric acid (w/w) to about 0.15% citric acid (w/w).

In some embodiments, the color of the composition is determined byvisual inspection. In some embodiments, the color is determined byassessing UV-vis absorbance values.

In some embodiments, after storage for at least one month at 65° C. thecomposition exhibits UV-vis absorbance values of 0.4 absorbance units(AU) or less at 400 nm; 0.1 AU or less at 500 nm; and/or 0.1 AU or lessat 600 nm. In some embodiments, after storage for at least one month at65° C. the composition exhibits UV-vis absorbance values of: 0.4 AU orless at 400 nm; 0.1 AU or less at 500 nm; and 0.1 AU or less at 600 nm.

In some embodiments, after storage for at least one month at 65° C. thecomposition exhibits UV-vis absorbance values of 0.2 AU or less at 400nm; 0.03 AU or less at 500 nm; and/or (iii) 0.03 AU or less at 600 nm.In some embodiments, after storage for at least one month at 65° C. thecomposition exhibits UV-vis absorbance values of: 0.2 AU or less at 400nm; 0.03 AU or less at 500 nm; and 0.03 AU or less at 600 nm.

In some embodiments, after storage for at least one month at 65° C. thecomposition exhibits UV-vis absorbance of 0.1 AU or less at 400 nm; 0.01AU or less at 500 nm; and/or (iii) 0.01 AU or less at 600 nm. In someembodiments, after storage for at least one month at 65° C. thecomposition exhibits UV-vis absorbance values of: 0.1 AU or less at 400nm; 0.01 AU or less at 500 nm; and (iii) 0.01 AU or less at 600 nm.

In some embodiments, the composition is a pharmaceutically acceptableformulation that is effectively absorbed in the treatment of the nail.

In a second aspect, the invention provides methods of treating orpreventing a fungal infection. The methods include administering atherapeutically effective amount of a formulation of the invention to apatient in need of such treatment.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows efinaconazole solutions exhibiting varying levels ofdiscoloration due to instability during storage.

FIG. 2A shows UV-vis absorbance values for efinaconazole solutionsexhibiting varying levels of discoloration, measured at 400 nm.

FIG. 2B shows UV-vis absorbance values for efinaconazole solutionsexhibiting varying levels of discoloration, measured at 500 nm.

FIG. 2C shows UV-vis absorbance values for efinaconazole solutionsexhibiting varying levels of discoloration, measured at 600 nm.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

As used herein, the term “pharmaceutical composition” refers to amixture containing a pharmaceutically active ingredient, such asefinaconazole, and one or more pharmaceutically acceptable excipients(antioxidants, preservatives, carriers, etc.). Compositions for topicaladministration are formulated as solutions, sprays, ointments, lotions,gels, shampoos, and the like. “Pharmaceutically acceptable” compositionsare those in which substituent components such as carriers, diluents,and excipients are compatible with each other and with the activeingredient. Pharmaceutically acceptable compositions are frequently madewith pharmaceutical-grade active agents and excipients. It will beunderstood that pharmaceutically acceptable compositions are notdeleterious to the recipient thereof.

As used herein, the term “efinaconazole” refers to(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine-1-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol,also known as KP-103, and pharmaceutically acceptable salts thereof.

As used herein, the term “absorbance” refers to the amount of visible orultraviolet light that is absorbed by a compound or a mixture ofcompounds. Absorbance can be determined using a UV-visiblespectrophotometer according to known techniques.

As used herein, the term “storage” refers to the holding of acomposition under controlled or uncontrolled conditions for a periodranging from a few minutes to several months or longer. Storageconditions that can be controlled include, for example, temperature,humidity, and the level of light. In many cases storage of apharmaceutical formulation is under industry acceptable standards and/orstandards that are mandated by regulatory agencies, such as US FDA.

As used herein, the term “treating” refers to an indicia of success inthe treatment or amelioration of a pathology, condition, or symptom,including any objective or subjective parameter such as abatement;remission; diminishing of symptoms or making the symptom, pathology orcondition more tolerable to the patient; and decreasing the frequency orduration of the symptom or condition. The treatment or amelioration ofsymptoms can be based on any objective or subjective parameter,including, e.g., the result of a physical examination. “Prevention” of adisease or condition or “prophylaxis” means reducing the probability ofonset of a condition or disease, delaying the time to onset of a diseaseor condition, reducing the duration of a subsequently arisingindication, and/or reducing the severity of a subsequently arisingcondition by administration of a composition to a subject that currentlydoes not have a disease or suffer from a condition. Prevention caninclude, but is not limited to, complete avoidance of the futureoccurrence (or recurrence) of a condition or disease. The inventionprovides both methods of treating and preventing fungal conditions inhumans.

As used herein, the term “fungal infection” refers to the unwantedgrowth of a fungus on the skin or nails of a person or animal. Fungalinfections are typically caused by fungi including Candida albicans,Cryptococcus neoformans, Aspergillus fumigatus, Trichophytonmentagrophytes, and the like. Compositions of the invention can beuseful in the treatment of, e.g., onychomycosis and various tinea typesof fungal infections, including tinea capitis and tinea pedis.

The terms “about” and “around,” as used herein to modify a numericalvalue, indicate a close range surrounding that explicit value. If “X”were the value, “about X” or “around X” would indicate a value from 0.9Xto 1.1X, and more preferably, a value from 0.95X to 1.05X. Any referenceto “about X” or “around X” specifically indicates at least the values X,0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and1.05X. Thus, “about X” and “around X” are intended to teach and providewritten description support for a claim limitation of, e.g., “0.98X.”

II. Anti-Fungal Compositions

In a first aspect, the invention provides a composition containing fromabout 0.5% to about 15% efinaconazole by weight, butylatedhydroxytoluene (BHT), and a salt of ethylenediaminetetraacetic acid(EDTA). The composition, if free of colorants (as will usually be thecase), is colorless at initial formulation and, after a period ofstorage of at least three weeks, will be colorless or have a pale yellowcolor. A composition in the context of the invention is typically aliquid (e.g., a solution) or a semi-solid composition (e.g., a gel,ointment, lotion, cream, or other form).

The determination of the color of a composition can be made by anysuitable method or combination of methods. It will be understood thatthe composition can be colorless or a have a color such as pale yellow,yellow, orange, amber, or brown. Frequently, compositions of theinvention are initially formulated such that they are both colorless, interms of color, and also transparent or clear, in terms of visiblematerial in the composition. Preferred compositions will remaincolorless and clear after storage for a period of time at relativelyhigh temperatures (e.g., temperatures of at least about 40° C., at leastabout 45° C., at least about 55° C., or higher, such as about 65° C.).In one aspect, color determination can be made by visual inspection.Visual inspection may include independent validation by a number ofpharmaceutical formulation scientists or other individuals (e.g., 2, 3,4, 5, 10, 20, 30, 50, or even more individuals). Human visual inspectionmay be made by comparison against standard (reference) color samplesthat aid in the determination of color. In another aspect, inspection ofthe color can be made by use of a device that measures color by anysuitable means, such as a colorimeter or by computer-based colorassessment methods. In a particular aspect, the determination of coloris made by UV/visual spectrum absorbance measurements, particularlywhere the UV-vis absorbance measurements have been standardized againstcompositions that have been determined to be good representatives ofclear, pale yellow (or another pale color), and unacceptable colors(such as dark orange). In a more particular aspect, the inventionprovides such compositions where after storage for at least one month at65° C. the composition exhibits one or more UV-vis absorbance valuesselected from the group consisting of: 0.4 absorbance units (AU) or lessat 400 nm; 0.1 AU or less at 500 nm; and 0.1 AU or less at 600 nm.

Components

In preferred embodiments, the compositions contain from about 0.5% (w/w)to about 15% (w/w) efinaconazole [i.e.,(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine-1-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol,also known as KP-103].

In some embodiments, the compositions of the invention contain fromabout 1% to about 12.5% efinaconazole by weight. The amount ofefinaconazole can be any amount that is suitable for the purpose of thecomposition. Typically, the amount of efinaconazole is an amount that iscapable of producing a therapeutic or prophylactic antifungal effect ina human patient. The amount of efinaconazole can vary with the nature ofthe composition, such as whether the composition is primarily comprisedof polar components, non-polar components, or a mix thereof and/or thedegree to which the efinaconazole API is soluble in the composition. Thecompositions can contain, for example, from about 1% to about 5%efinaconazole, such as where the composition primarily contains polarcomponents and/or where the efinaconazole is relatively highly solublein the composition. The composition can contain from about 5% to about10% efinaconazole where the composition contains significantly morenon-polar components and/or where the efinaconazole is relatively lesssoluble in the composition. In some embodiments, the invention providescompositions that contain from about 7.5% to about 10.0% efinaconazole,from about 10% to about 15%, from about 2% to about 8% efinaconazole, orfrom about 4% to about 6% efinaconazole. Other ranges of efinaconazolebetween about 0.5% and about 15% can be suitable, depending on theidentities and quantities of the other components in the compositions.In some embodiments, the compositions contain about 0.5%, 0.75%, 0.8%,0.9%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%,6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%,12.5%, 13%, 13.5%, 14%, 14.5%, or about 15% efinaconazole by weight.

The classification of components of a composition as either polar ornon-polar can be determined by formulation scientists. In general, polarsolvents will be miscible with water and miscible with non-polarsolvents. Examples of polar components that are regularly found inpharmaceutical and other formulations include ethanol, propylene glycol,glycerin, triacetin, water, and isopropyl alcohol. Examples of non-polarcomponents include capric/caprylic triglycerides, myristyl lactate,diisopropyl adipate, isopropyl myristate, and cyclomethicone.

Compositions of the invention contain butylated hydroxytoluene (BHT) inan amount that, in combination with the amount of EDTA in thecomposition, is capable of maintaining color stability of theefinaconazole composition such that after a period of three weeks, onemonth, or longer, even at relatively high temperatures (e.g., about 40°C., about 50° C., about 60° C., about 65° C., or higher) the compositionmaintains a colorless or pale yellow color, as determined by visualinspection, UV-visual spectrum data, or other suitable color measurementmethods. The amount of BHT can vary with the amount of EDTA present, theamount of efinaconazole, and the nature of the composition and the othercomponents of the composition. The compositions can contain, forexample, from about 0.01% to about 2% BHT, from about 0.01% to about 1%BHT, from about 1% to about 2% BHT, from about 0.5% to about 1.5% BHT,or from about 0.75% to about 1.25% BHT. In some embodiments, thecompositions contain about 0.01%, 0.05%, 0.10%, 0.15%, 0.20%, 0.25%,0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.55%, 0.60%, 0.65%, 0.70%, 0.75%,0.80%, 0.85%, 0.90%, 0.95%, 1.00%, 1.05%, 1.10%, 1.15%, 1.20%, 1.25%,1.30%, 1.35%, 1.40%, 1.45%, 1.50%, 1.55%, 1.60%, 1.65%, 1.70%, 1.75%,1.80%, 1.85%, 1.90%, 1.95%, or about 2.00% BHT by weight.

Preferred compositions contain a salt of ethylenediaminetetraacetic acid(EDTA). The salt of ethylenediaminetetraacetic acid can be any suitablesalt. In general, the salt will be one that is acceptable forpharmaceutical formulations and compatible with efinaconazole.Frequently used salts are the disodium and tetrasodium salts ofethylenediaminetetraacetic acid. The amount of EDTA, or a salt thereof,can be any amount that in combination with the amount of BHT provides acolorless composition on initial formulation and maintains a colorlessto pale yellow formulation at relatively high temperatures (e.g., atleast about 40, at least about 50, or at least about 60° C.) for periodsof at least about 3 weeks (e.g., at least about 4 weeks, at least about6 weeks, at least about 8 weeks, at least about 10 weeks, at least about12 weeks, at least about 4 months, at least about 6 months, or longer).Typically compositions according to the invention will contain fromabout 0.0001% to about 1% EDTA, or a salt thereof. The amount of EDTA orEDTA salt used will vary depending on factors including the amount ofefinaconazole, the amount of BHT, and the nature of the formulation. Forexample, in a gel formulation the amount of EDTA or EDTA salt used willtypically be higher than the amount used in a solution. Also, the amountof EDTA or EDTA salt that is used in a non-aqueous formulation or lowwater content formulation can be lower than the amount of EDTA or EDTAsalt that is used in a formulation with higher water content. Thus, insome embodiments, the amount of EDTA or EDTA salt in a composition ofthe invention is between about 0.1% and about 1% by weight (e.g., about0.2%-1%, about 0.25-0.75%, about 0.3-0.8%, or about 0.4-0.7%, such as0.15%, 0.35%, 0.45%, 0.5%, 0.6%, 0.7%, or 0.9%). Such amounts are usefulin, e.g., gel compositions. In some embodiments, the amount of EDTA orEDTA salt is between about 0.004% and about 0.2%, such as about 0.175%,about 0.15%, about 0.125%, or about 0.1%.

The inventors also have surprisingly found that in certain formulationsthe amount of EDTA or EDTA salt can be in the range of only about0.0001% to about 0.0005%, such as from about 0.0001% to about 0.00025%,from about 0.00025% to about 0.00050%, or from about 0.0002% to about0.0004% EDTA or EDTA salt. In particular embodiments, the compositionscontain about 0.00010%, 0.00012%, 0.00014%, 0.00016%, 0.00018%,0.00020%, 0.00022%, 0.00024%, 0.00026%, 0.00028%, 0.00030%, 0.00032%,0.00034%, 0.00036%, 0.00038%, 0.00040%, 0.00042%, 0.00044%, 0.00046%,0.00048%, or about 0.00050% EDTA or EDTA salt by weight. In particularembodiments, the amount of EDTA or EDTA salt included in the compositionis in the range of about 0.0001% (w/w) to about 0.0005% (w/w) (e.g.,0.0002% or 0.0004%) and the amount of BHT is in the range of about 0.01%(w/w) to about 2% (w/w) (e.g., 0.02%, 0.04%, 0.05%, 0.07%, 0.08%, 1.0%,1.2%, 1.4%, 1.5%, 1.7%, or 1.9%).

In some exemplary embodiments, the invention provides compositionswherein the amount of EDTA or EDTA salt is in the range of about 0.0001%(w/w) to about 0.0005% (w/w) and the amount of BHT is in the range ofabout 0.01% (w/w) to about 2% (w/w).

In some exemplary embodiments, the invention provides compositionswherein the amount of EDTA or EDTA salt is in the range of about 0.0001%(w/w) to about 0.0003% (w/w) the amount of BHT is in the range of about0.05% (w/w) to about 0.15%. In some exemplary embodiments, the inventionprovides compositions wherein the amount of EDTA or EDTA salt is in therange of about 0.1% to about 1.0% by weight (e.g., about 0.15% w/w toabout 0.75% w/w), the amount of BHT is in the range of about 0.01% (w/w)to about 2% (w/w) (e.g., about 0.02% or 0.025% to about 1.0% or 1.5%w/w), and the amount of efinaconazole is the range of about 0.5% (w/w)to about 5% (w/w) (e.g., about 1%, about 2%, or about 3%).

In some exemplary embodiments, the invention provides compositionswherein the amount of EDTA or EDTA salt is about 0.00025% (w/w) and theamount of BHT is about 0.1% (w/w).

The compositions of the invention can contain a polar solvent, anon-polar solvent, or a mixture of the two. In some embodiments, thecomposition includes a polar solvent system containing propylene glycol,glycerin, and ethanol. In some embodiments, the composition includes anon-polar solvent system containing C₁₂₋₁₅ alkyl lactate, diisopropyladipate, cyclomethicone, and ethanol.

Compositions of the invention can contain, and often will contain,citric acid. Particularly where the composition includes the polarsolvent system, citric acid is also present because the inventors havefurther surprisingly found that the presence of citric acid also aids inmaintaining color stability in such compositions as compared tocompositions containing the non-polar solvent system wherein citric acidmay not be required to maintain color stability (and as compared tocompositions that include a polar solvent system and do not includecitric acid). Even in compositions that include a non-polar solventsystem, the inventors have found that the presence of citric acid as astabilizer, chelating agent (chelator), anti-oxidant, and/or pHadjusting agent, or otherwise does not significantly detract from colorstability in compositions containing the non-polar solvent system.

The amount of citric acid can be any amount that when combined with theEDTA and BHT either results in acceptable color stability, while usuallyalso providing a detectable anti-oxidant effect, or that preferablyenhances the color stability of the composition over the colorstabilizing effects of BHT and EDTA alone. Compositions according tosuch aspects of the invention can contain, for example, from about 0.01%citric acid to about 1% citric acid by weight. The compositions cancontain from about 0.02% to about 0.5% citric acid, from about 0.05% toabout 1.5% citric acid, from about 0.08% to about 0.8% citric acid, orfrom about 0.085% to about 0.5%, 0.4%, 0.3%, or 0.1% citric acid. Insome embodiments, the compositions contain about 0.05%, 0.06%, 0.07%,0.08%, 0.09%, 0.10%, 0.12%, 0.15%, 0.17%, 0.20%, 0.25%, 0.30%, 0.35%,0.40%, 0.45%, 0.50%, 0.55%, 0.60%, 0.65%, 0.70%, 0.75%, 0.80%, 0.85%,0.90%, 0.95%, or about 1.00% citric acid by weight. As for BHT and EDTA,ordinarily skilled formulation scientists will be capable of determiningappropriate amounts of citric acid to include in any particularefinaconazole composition given the guidance provided here with respectto color stability.

In some embodiments, the composition contains: from about 0.5% to about15% efinaconazole by weight, such as from about 0.75% to about 12%efinaconazole by weight (e.g., about 1-5% or about 5-10% efinaconazoleby weight), from about 0.01% to about 2% BHT by weight (e.g., about 0.2%to about 1.5% BHT by weight), and from about 0.0001% to about 1.5% EDTAor EDTA salt by weight (e.g., about 0.0001% to about 0.0005% EDTA orEDTA salt by weight or about 0.1% to about 1.25% EDTA or EDTA salt byweight), and about 0.1% to about 1% citric acid by weight.

In some exemplary embodiments, the composition contains: from about 0.5%to about 15% efinaconazole by weight, from about 0.01% to about 2% BHTby weight, from about 0.0001% to about 0.0005% EDTA or EDTA salt byweight, and from about 0.1% to about 1% citric acid by weight.

In some exemplary embodiments, the composition contains from about 0.5%to about 15% efinaconazole by weight, about 0.1% BHT by weight, andabout 0.00025% EDTA or EDTA salt by weight. In some embodiments, thecomposition further contains about 0.1% citric acid by weight.

In some exemplary embodiments, the composition contains from about 0.5%to about 15% efinaconazole by weight, about 0.1% BHT by weight, about0.00025% EDTA or EDTA salt by weight, and about 0.1% citric acid byweight.

In some embodiments, the composition contains about 10% efinaconazole byweight. In some embodiments, the composition contains about 5%efinaconazole by weight. In some embodiments, the composition containsabout 2% efinaconazole by weight.

Compositions can include additional components that are compatible withthe efinaconazole, BHT, EDTA, and, if present, citric acid components ofthe composition, and that preferably do not materially affect the basicand novel properties of the inventive compositions, such as the colorstability of the composition. Often compositions will includeco-solvents, which can be non-polar or polar and/or volatile ornon-volatile. Further components are described in detail below.

Composition Color

The compositions of the invention typically exhibit color stability overextended storage periods. The compositions can be stable for periodslasting from about two weeks to several months or even years (e.g.,about one year, about two years, or even about three years, or longer,at room temperature storage). The compositions can be shelf-stable, forexample, for at least a month, or at least 3 months, or at least 6months, or at least 9 months, or at least a year at temperatures thatare higher than room temperature (RT), such as at least about 35° C., atleast about 45° C., at least about 50° C., at least about 55° C., atleast about 60° C., or higher. The compositions can be stored at aroundroom temperature (i.e., 25° C.), at around 40° C., at around 65° C., orat other suitable temperatures.

It will be appreciated by those of skill in the art that the stabilityof a composition can be readily assessed by eye, which is a method usedoften in the assessment of color stability of products such aspharmaceutical compositions. In some embodiments, discoloration can bequantified by recording a measurement, such as the UV-vis absorbance ofa composition or a diluted sample of the composition, which provides amore quantitative measure of color stability. In cases where absorbanceof UV/visible light is used to assess color stability, the absorbancecan be recorded at any suitable wavelength and using any suitable deviceor method. Useful absorbance measurements for efinaconazole compositionscan be recorded at 400 nm, 500 nm, or 600 nm. Other wavelengths can beused for measurement, depending on the particular composition beinganalyzed and the concentrations of the composition components.Compositions that do not exhibit discoloration remain colorless.Compositions that remain colorless over extended periods areparticularly preferred. Typically, colorless compositions have UV-visabsorbance values below 0.1 absorbance units (AU) at 400 nm, below 0.01AU at 500 nm, and below 0.01 AU at 600 nm. Certain acceptablecompositions exhibit a slight change in color. Such composition may turnpale yellow during storage. Typically, pale yellow compositions haveUV-vis absorbance values below 0.2 AU at 400 nm, below 0.1 AU at 500 nm,and below 0.1 AU at 600 nm. One of skill in the art will appreciate thatcolorless and pale yellow compositions can be identified by visualinspection without the use of UV-vis measurements.

As noted above, in some embodiments the determination of color stabilityis made using a device that can quantify the color of the compositionafter a time of storage as compared to its initial color and/or againststandard ranges that reflect acceptable color (usually as compared tocontrols and run with two or more samples). Any suitable device andmeasurement system can be used. Typically, ultraviolet-visible (UV-vis)absorbance units (AUs) determined by a spectrophotometer or similardevice can be determined for a composition and assessed against AUvalues that provide a range, number, and/or cutoff that is deemed toreflect acceptable color stability in a composition. The range, cutoff,and/or value can change with various factors such as the wavelength atwhich the measurement is taken. In some aspects, multiple measurementsat different wavelengths are performed. In some aspects, only a singlemeasurement at a single wavelength is performed. In one exemplaryembodiment, after storage for at least one month at 65° C. thecomposition exhibits UV-vis absorbance values of: 0.4 absorbance units(AU) or less at 400 nm; 0.1 AU or less at 500 nm; and 0.1 AU or less at600 nm.

The compositions exhibit certain UV-vis absorbance values after storagefor at least one month at 65° C. In preferred embodiments, thecomposition exhibits one or more UV-vis absorbance values selected from:0.4 AU or less at 400 nm; 0.1 AU or less at 500 nm; and 0.1 AU or lessat 600 nm. In some embodiments, after storage for at least one month at65° C. the composition exhibits UV-vis absorbance values of: 0.4absorbance units (AU) or less at 400 nm; 0.1 AU or less at 500 nm; and0.1 AU or less at 600 nm.

The UV-vis absorbance of a composition or sample of a composition at 400nm can be, for example, from about 0.1 AU to about 0.2 AU, or from about0.2 AU to about 0.4 AU. The UV-vis absorbance at 400 nm can be about0.1, 0.15, 0.2, 0.25, 0.3, 0.35 or about 0.4 AU.

The UV-vis absorbance of a composition or sample of a composition at 500nm can be, for example, from about 0.01 AU to about 0.05 AU, or fromabout 0.05 AU to about 0.1 AU. The UV-vis absorbance at 500 nm can beabout 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09 or about 0.1AU.

The UV-vis absorbance of a composition or sample of a composition at 600nm can be, for example, from about 0.01 AU to about 0.05 AU, or fromabout 0.05 AU to about 0.1 AU. The UV-vis absorbance at 600 nm can beabout 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09 or about 0.1AU.

In some embodiments, after storage for at least one month at 65° C. thecomposition exhibits one or more UV-vis absorbance values selected from:0.2 absorbance units (AU) or less at 400 nm, 0.03 AU or less at 500 nm,and (iii) 0.03 AU or less at 600 nm. In some embodiments, after storagefor at least one month at 65° C. the composition exhibits UV-visabsorbance values of: 0.2 absorbance units (AU) or less at 400 nm; 0.03AU or less at 500 nm; and 0.03 AU or less at 600 nm.

In some embodiments, after storage for at least one month at 65° C. thecomposition exhibits one or more UV-vis absorbance values selected from:0.1 absorbance units (AU) or less at 400 nm, 0.01 AU or less at 500 nm,and (iii) 0.01 AU or less at 600 nm. In some embodiments, after storagefor at least one month at 65° C. the composition exhibits UV-visabsorbance values of: 0.1 absorbance units (AU) or less at 400 nm, 0.01AU or less at 500 nm, and (iii) 0.01 AU or less at 600 nm.

The absorbance values described herein can also be exhibited afterstorage for 6 weeks, or 8 weeks, or 3 months, or 6 months, or 1 year, orlonger.

Discoloration (or a lack thereof) can also be assessed by comparing aUV-vis absorbance value for a composition after a period of storage to aUV-vis absorbance value for the composition before the period ofstorage. In some embodiments, for example, the absorbance of a sample ofthe composition at 400 nm after storage for a set period is not morethan 5 times the absorbance of the sample at 400 nm before the setperiod. In some embodiments, the absorbance of a sample of thecomposition at 500 nm after storage for a set period is not more than 10times the absorbance of the sample at 500 nm before the set period. Insome embodiments, the absorbance of a sample of the composition at 600nm after storage for a set period is not more than 5 times theabsorbance of the sample at 600 nm before the set period. In someembodiments, a sample of the composition appears very light yellow aftera set storage period. In some embodiments, a sample of the compositionappears colorless after a set storage period.

A sample can be any portion of a composition that is held for storageand/or analysis. The sample can consist of a composition of theinvention as described herein, or a composition that has been diluted orconcentrated as necessary to facilitate analysis. The storage period canbe any length of time suitable for assessing the effects of storage onthe physical and/or chemical properties of a composition. In someembodiments, the storage period is at least 4 weeks long. In someembodiments, the storage is conducted at a temperature of from about 20°C. to about 8° C. In some embodiments, the storage is conducted at atemperature of about 65° C.

Formulations

In general, the compositions of the invention are formulated to beadministered topically. The compositions can be formulated, for example,as solutions, sprays, ointments, lotions, gels, shampoos, and the like.The compositions can also be formulated according to U.S. Pat. No.8,486,978, as well as according to U.S. Pat. Appl. Pub. Nos.2009/0175810 and 2014/0228403, the entirety of which are incorporatedherein by reference in their entirety. The compositions of the presentinvention, however, generally exhibit enhanced stability when comparedto known formulations. In a preferred embodiment, the composition isformulated as a solution. In some embodiments, preferred componentsinclude volatile solvents, non-volatile solvents, and wetting agents.

Volatile solvents are compounds which have a measurable vapor pressure,and preferably are compounds that have a vapor pressure of greater thanabout 100 Pa at room temperature. Examples of volatile solvents include:acetone, 2-amino-2-methyl-1-propanol, 1,2-butanediol, 1,4-butanediol,2-butanol, ethanol, ethyl acetate, n-heptane, isobutanol, isopropylalcohol, 1-propanol, 2-propanol, and water.

Examples of suitable non-volatile solvents include, but are not limitedto, squalane, dibutyl sebacate, isopropyl laurate, isopropyl myristate,isopropyl palmitate, isopropyl stearate, myristyl alcohol, oleylalcohol, oleic acid, lauryl lactate, myristyl lactate, mixed C12-15alkyl lactates, diisopropyl adipate, octyldodecanol, caproic acid,caprylic acid, capric acid, lauryl benzoate, myristyl benzoate, mixedC12-15 alkyl benzoates, benzyl benzoate, tridecyl neopentanoate, lightmineral oil, mineral oil, alpha terpineol, diethylene glycol monoethylether, n-methylpyrrolidone, dimethyl sulfoxide, ethyl lactate, propyleneglycol, hexylene glycol, glycerol (glycerin), benzyl alcohol andglycerol triacetate.

Useful wetting agents are chemical compounds that reduce the surfacetension of liquid compositions and do not build viscosity. Anysurfactant or group of surfactants that is suitable for dermatologicapplications is suitable for the invention. Such surfactants mayfunction as wetting agents in the compositions of the invention, and asemulsifiers or solubilizers. The surfactants may be nonionic, anionic,cationic, zwitterionic, amphoteric, or ampholytic surfactants.

In some embodiments, the wetting agent is a volatile silicone. Suchvolatile silicones include linear or cyclic polyorganosiloxane compoundsof formula [R^(a)SiOR^(b)]_(n) wherein n is less than or equal to 6, andR^(a) and R^(b) are independently selected alkyl groups. A volatilesilicone has a measurable vapor pressure under ambient conditions.Examples of cyclic volatile silicones includepolydimethylcyclosiloxanes, generally known as cyclomethicones (such ascyclopentasiloxane, cyclotetrasiloxane, decylmethylcyclopentasiloxane,and the like). Examples of linear volatile silicones include linearpolysiloxanes (such as hexamethyldisiloxane, octamethyltrisiloxane, andthe like).

In some embodiments, the invention provides a pharmaceutical compositionfor treatment of a disorder of the nail or nail bed comprisingefinaconazole, EDTA or a salt thereof, BHT, and optionally citric acidas described above, and further comprising an alcohol, a volatilesilicone, and one or more esters of the formula RCO—OR′, wherein R andR′ may be identical or different and each of R and R′ represents alinear or branched chain of an alkyl, alkenyl, alkoxycarbonylalkyl, oralkoxycarbonyloxyalkyl radical having from 1 to 25 carbon atoms. In someembodiments, the volatile silicone is present in the composition at aconcentration less than 25% w/w. In some embodiments, the concentrationof volatile silicone is less than 15%. In some embodiments, the ratio ofthe alcohol to volatile silicone in the composition % w/w is at least2:3. In some embodiments, the ratio of the alcohol to volatile siliconeis at least 3:1. In certain embodiments, the composition does not form afilm when topically applied to the surface of a nail. In certainembodiments, the composition is free of polymeric film formingcompounds.

In some embodiments, the invention provides a pharmaceutical compositionfor treatment of a disorder of the nail or nail bed comprisingefinaconazole, EDTA or a salt thereof, BHT, and optionally citric acidas described above, and further comprising:

-   -   alcohol—10% to 80% (w/w);    -   cyclomethicone—0.01% to less than 25% (w/w); and    -   diisopropyl adipate plus either or both of C12-15 alkyl lactate        and isopropyl myristate −5% to 90% (w/w).

In some embodiments, the invention provides a pharmaceutical compositionfor treatment of a disorder of the nail or nail bed comprisingefinaconazole, EDTA or a salt thereof, BHT, and optionally citric acidas described above, and further comprising:

-   -   alcohol—50% to 70% (w/w);    -   cyclomethicone—10% to 15% (w/w);    -   diisopropyl adipate—8% to 15% (w/w); and    -   either or both of C12-15 alkyl lactate and isopropyl        myristate—8% to 15% (w/w).

In certain embodiments, the composition of the invention is free ofpolymeric film forming compounds and does not form a solid film or hardlacquer or shell when applied to the surface of a nail. Formation of alacquer, shell, or film occurs by a process of solvent casting followingevaporation of a volatile solvent which leaves behind the polymeric filmformer as a solid residue. Nail lacquers containing polymeric filmformers are described, for example, in U.S. Pat. Nos. 4,957,730;5,120,530; 5,264,206; 5,346,692; and 5,487,776; the entirety of whichpatents are incorporated herein by reference. Examples of polymeric filmforming compounds include polymers and copolymers of polyvinyl acetate,polyvinylpyrrolidone, methacrylic acid, polyvinyl butyrals, polyvinylacetals, and cellulose derivatives such as cellulose acetate phthalate,cellulose acetate butyrate, cellulose acetate propionate, cellulosenitrate, cellulose sulfate, ethylcellulose, and cellulose acetate. Apolymeric film forming agent can be present in the composition of theinvention, however, if it is present in an amount below that which willresult in the formation of a film or lacquer following application ofthe composition to the surface of a nail. In some embodiments, thepharmaceutical composition further comprises a thickening agent such asan acrylate crosspolymer (e.g., acrylates/C10-30 alkyl acrylatecrosspolymer; sold under tradenames including CARBOPOL 1342). Those ofskill in the art will appreciate that acrylate crosspolymers used in thepresent invention break upon contact with the surface of the skin andnails and do not form a film, hard shell, or lacquer.

The composition of the invention can contain other components, such aspreservatives, lubricants, humectants, moisture regulators, foamingagents, binders, pH regulators, osmotic pressure modifiers, emulsifiers,colors, aerosol propellants, fragrances, or odor maskers. Those of skillin the art are aware of the components that are useful for a chosenformulation. Such components are described in sources such as Remington:The Science and Practice of Pharmacy, 20^(th) ed., 2000. Usefulcombinations for the compositions of the invention includewater/propylene glycol/glycerin/ethanol, water/C₁₂₋₁₅ alkyllactate/diisopropyl adipate/cyclomethicone/ethanol, and other mixtures.

Accordingly, some embodiments of the invention provide compositionsformulated as solutions. In some embodiments, the composition containsone or more components selected from a volatile solvent, a non-volatilesolvent, and a wetting agent. In some embodiments, the compositioncontains one or more components selected from water, propylene glycol,glycerin, and ethanol. In some embodiments, the composition contains oneor more components selected from water, C₁₂₋₁₅ alkyl lactate,diisopropyl adipate, cyclomethicone, and ethanol.

III. Methods of Treatment

In another aspect, the invention provides methods for treatingconditions of the skin or nails. The methods include topicallyadministering a composition of the invention to a patient in needthereof. In general, the skin and nail conditions are caused by fungiincluding Candida albicans, Cryptococcus neoformans, Aspergillusfumigatus, Trichophyton mentagrophytes, and the like. Examples of skinand nail conditions include, but are not limited to, tinea pedis(athlete's foot), tinea capitis (scalp ringworm), onychomycosis (tineaunguium), tinea cruris (jock itch), tinea corporis (ringworm), and yeastinfections.

Tinea pedis is a fungal infection of the feet caused by Trichophytonrubrum or Trichophyton mentagrophytes. Tinea pedis can occur on theheel, on the plantar region of the sole, and on or between the toes.Tinea capitis is an infection of the scalp caused by Microsporumaudouinii, Microsporum canis, Trichophyton tonsurans, Trichophytonviolaceum, Trichophyton schoenlenii, and the like. Onychomycosis is aninfection of the nail or nail bed caused by Trichophyton rubrum,Trichophyton interdigitale (Trichophyton mentagrophytes), Epidermophytonfloccosum, Trichophyton violaceum, Microsporum gypseum, Trichophytontonsurans, Trichophyton soudanense, and Candida species.

According to the methods of the invention, the compositions aretopically applied to the affected area (such as the feet, scalp, orhands) at least three times a week for a period of from about one weekto about 12 weeks, or until the disappearance of the condition. In someembodiments, the composition is applied once daily for about one totwelve weeks. In some embodiments, the composition is applied twicedaily for about one to twelve weeks. Other dosing regimens can be usedin the methods of the invention, depending on the type of fungus causingthe condition and the severity of the condition.

The following examples are intended to illustrate, but not to limit, theaspects of the invention described above.

IV. Examples

Solutions were prepared by combining efinaconazole and various solvents,resulting in mixtures to which antioxidants, hydroxy acids, andchelators were added as described below. Resulting solutions were clearand colorless when all components were first combined. The solutionswere stored at 65° C. Over the storage period, certain solutions wereobserved to turn a pale yellow color. The color of certain solutionsdeepened to shades of yellow, light orange, dark orange, pink, copper,light red, and dark red. A photograph of solutions exhibiting variouscolors is shown in FIG. 1. UV-visible absorption spectra were recordedat various time points using a Varian Cary 50 Bio Spectrophotometer.Samples were scanned over 300 nm to 800 nm. Absorbance values were notedat 400, 500 and 600 nm. Based on the absorbance readings, the “time tofailure” was determined using cutoff values of 0.1407 absorbance units(AU) at 400 nm, 0.0290 AU at 500 nm, and 0.0290 AU at 600 nm.

Examples 1-6, formulated as shown in Table 1, contained 10%efinaconazole by weight and various antioxidants in a water/alkyllactate/diisopropyl adipate/cyclomethicone/ethanol solvent system. Theresults summarized in Table 2 show that UV absorbance values exceededacceptable limits, reflecting unacceptable levels of color change in theformulation, within 2 weeks (Examples 1 and 5), and—in the case ofpropyl gallate—within only 4 days (Example 3).

TABLE 1 Example No. (% w/w) Ingredients 1 2 3 4 5 6 EDTA disodium0.00025 0.00025 0.00025 0.00025 0.00025 Purified Water 1.00 1.00 1.001.00 1.00 Citric Acid Anhydrous 0.10 0.10 0.10 0.10 0.10 BHA 0.10 PropylGallate 0.10 0.10 Ascorbic Acid 0.10 Ascorbyl Palmitate 0.10 0.20 C12-15Alkyl Lactate 10.00 10.00 10.00 10.00 10.00 10.00 Ceraphyl 230(Diisopropyl 12.00 12.00 12.00 12.00 12.00 12.00 Adipate) Cyclomethicone13.00 13.00 13.00 13.00 13.00 13.00 KP-103 10.00 10.00 10.00 10.00 10.0010.00 Alcohol, 190 Proof Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. to 100 to 100 to100 to 100 to 100 to 100

TABLE 2 Time to Absorbance DESCRIPTION 1 month Failure 400 nm 500 nm 600nm 1 citric acid, Yellow 2 wk >0.1407 @ 400 nm EDTA, BHA >0.0290 @ 500nm 2 citric acid, Yellow 1 wk >0.0290 @ 600 nm EDTA, PROPYL GALLATE 3propyl gallate Orange/ 4 days Red 4 citric acid, Yellow 1 wk EDTA,ascorbic acid 5 citric acid, Yellow 2 wk EDTA, ascorbyl palmitate 6citric acid, Yellow 1 wk EDTA, ascorbyl palmitate

Examples 7-14, formulated as shown in Table 3, contained 10%efinaconazole by weight in the water/alkyl lactate/diisopropyladipate/cyclomethicone/ethanol solvent system. The results summarized inTable 4 show that the compositions containing EDTA/BHT did not changesignificantly in color for over a month when stored at 65° C. (Examples7 and 14). Citric acid can be included as an additional component in theEDTA/BHT formulations. Taken together, examples 7-14 show that BHT is auniquely useful stabilizer for efinaconazole formulations, particularlywhen combined with EDTA and citric acid. The stability observed forformulations containing BHT was particularly unexpected given theinstability observed for formulations containing BHA and propyl gallate.

TABLE 3 Example No. (% w/w) Ingredients 7 8 9 10 11 12 13 14 EDTAdisodium 0.00025 0.00025 0.00025 0.00025 Purified Water 1.00 1.00 1.001.00 1.00 1.00 Citric Acid Anhydrous 0.10 0.10 0.10 0.10 BHT 0.10 0.100.10 0.10 C12-15 Alkyl Lactate 10.00 10.00 10.00 10.00 10.00 10.00 10.0010.00 Ceraphyl 230 12.00 12.00 12.00 12.00 12.00 12.00 12.00 12.00(Diisopropyl Adipate) Cyclomethicone 13.00 13.00 13.00 13.00 13.00 13.0013.00 13.00 KP-103 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00Alcohol, 190 Proof Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. to 100 to 100to 100 to 100 to 100 to 100 to 100 to 100

TABLE 4 Time to Absorbance No DESCRIPTION 1 month Failure 400 nm 500 nm600 nm 7 citric acid, V. Light >1 mo 0.1407 0.029 0.029 EDTA, BHT Yellow8 citric acid, Yellow 1 wk >0.1407 @ 400 nm EDTA >0.0290 @ 500 nm 9citric acid Yellow 1 wk >0.0290 @ 600 nm 10 EDTA Copper 1 wk 11 BHTCopper 1 wk 12 No stabilizers Orange 1 wk 13 BHT + citric Yellow 3 wk *acid 14 BHT + EDTA CC >1 mo 0.0414 0.0042 0.0082

Examples 15-19, formulated as shown in Table 5, contained 10%efinaconazole by weight and various acid components in the water/alkyllactate/diisopropyl adipate/cyclomethicone/ethanol solvent system. Theresults summarized in Table 6 show that the citric acid/EDTA/BHTformulation remained clear and colorless for over a month when stored at65° C. (Example 19). For the other acid components, absorbance valuesexceeded acceptable limits within 2 or 3 weeks. Formulations accordingto Example 19 are particularly useful for the treatment ofonychomycosis.

TABLE 5 Example No. (% w/w) Ingredients 15 16 17 18 19 EDTA disodium0.00025 0.00025 0.00025 0.00025 0.00025 Purified Water 1.00 1.00 1.001.00 1.00 Citric Acid Anhydrous 0.10 Acetic Acid 0.10 Lactic Acid 0.10Tartaric Acid 0.10 Salicylic Acid 0.10 BHT 0.10 0.10 0.10 0.10 0.10C12-15 Alkyl Lactate 10.00 10.00 10.00 10.00 10.00 Ceraphyl 230(Diisopropyl 12.00 12.00 12.00 12.00 12.00 Adipate) Cyclomethicone 13.0013.00 13.00 13.00 13.00 KP-103 10.00 10.00 10.00 10.00 10.00 Alcohol,190 Proof Q.S. to Q.S. to Q.S. to Q.S. to Q.S. to 100 100 100 100 100

TABLE 6 Time to Absorbance No DESCRIPTION 1 month Failure 400 nm 500 nm600 nm 15 EDTA, BHT, Yellow 2 wk >0.1407 @ 400 nm acetic acid >0.0290 @500 nm 16 EDTA, BHT, Yellow 2 wk >0.0290 @ 600 nm lactic acid 17 EDTA,BHT, Light 3 wk tartaric acid Yellow 18 EDTA, BHT, Light 3 wk salicylicacid Yellow 19 EDTA, BHT, CC >1 mo 0.0414 0.0042 0.0082 citric acid

Examples 20-26, formulated as shown in Table 7, contained 10%efinaconazole by weight in a second solvent system. Example 27 contained5% efinaconazole. As shown in Table 8, absorbance for all of the samplesexcept for Example 20 exceeded acceptable absorbance levels within 4days to 3 weeks. Example 20, containing citric acid, EDTA, and BHTremained clear and colorless for over one month when stored at 65° C.

TABLE 7 Example No. (% w/w) Ingredients 20 21 22 23 24 25 26 27 EDTAdisodium 0.00025 0.00025 0.00025 0.00025 Purified Water 1.00 1.00 1.001.00 Citric Acid Anhydrous 0.10 0.10 0.10 0.10 BHT 0.01 0.10 0.10 0.100.10 Propylene Glycol 34.40 34.50 35.00 34.50 35.00 34.50 35.00 37.95Glycerin 27.20 27.20 27.40 27.20 27.50 27.30 27.50 28.45 Vitamin E 0.05KP-103 10.00 10.00 10.00 10.00 10.00 10.00 10.00 5.00 Alcohol, 190 ProofQ.S. Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. to 100 to 100 to 100 to 100 to100 to 100 to 100 to 100

TABLE 8 Time to Absorbance No DESCRIPTION 1 month Failure 400 nm 500 nm600 nm 20 CA, EDTA, V. Light >1 mo 0.1407 0. 029 0.029 BHT Yellow 21citric acid, Orange/Red 4 days >0.1407 @ 400 nm EDTA >0.0290 @ 500 nm 22citric acid, Orange/Red 2 wk >0.0290 @ 600 nm BHT 23 EDTA, BHT LightCopper 3 wk 24 citric acid Orange/Red 4 days 25 EDTA Orange/Red 1 wk 26BHT Orange 2 wk 27 vitamin E, Pinkish/Red* <2 wk BHT

Examples 28-33, as shown in Table 9, contained 2% efinaconazole byweight in gel formulations. As shown in Table 9, most formulationscontaining BHT and EDTA remained clear and colorless for 8 weeks.Example 9, without citric acid, gained only a very light color between 4and 8 weeks.

TABLE 9 Contents BHT EDTA Citric acid Color after storage at 65° C. No.(%/w/w) (%/w/w) (% w/w) Initial 1 wk 2 wk 4 wk 8 wk 28 0.1 0.1 0.2 CC CCCC CC CC 29 0.0 0.1 0.2 CC Dark Yellow Orange Light Amber Amber 30 0.10.1 0.0 CC CC CC CC Light Yellow 31 0.0 0.0 0.0 CC Orange Light AmberAmber Amber 32 0.5 0.1 0.2 CC CC CC CC CC 33 0.1 0.1 0.5 CC Not CC CC CCdetermined (3 wks) (7 wks)

Examples 34-39, as shown in Table 10, contained 2% efinaconazole byweight in additional gel formulations. Color of certain formulations wasassessed by visual observation and the results are presented in Table11. The excipients described in these formulations, as with otherformulations provided herein, can be replaced with other knownformulations having similar functions to generate additional suitableformulations according to the invention, but typically the EDTA andcitric acid elements are maintained, along with the efinaconazole API.

TABLE 10 Example No. (% w/w) Component 34 35 36 37 38 39 Efinaconazole2.00 2.00 2.00 2.00 2.00 2.00 Propylene 20.00 20.00 20.00 20.00 20.0020.00 glycol Alcohol, 190 8.00 8.00 8.00 8.00 8.00 8.00 proof Diethylene20.00 20.00 20.00 20.00 20.00 20.00 glycol monoethyl ether Hexylene12.00 12.00 12.00 12.00 12.00 12.00 glycol Acrylates/C10- 2.00 2.00 2.002.00 2.00 2.00 30 alkyl acrylate crosspolymer Niacinamide 2.00 2.00 2.002.00 2.00 2.00 Butylated 0.10 — 0.10 — 0.50 0.10 hydroxytoluene Edetate0.1 0.1 0.1 — 0.1 0.1 disodium Citric acid, 0.2 0.2 — — 0.1 0.5anhydrous Purified water qs 100 qs 100 qs 100 qs 100 qs 100 qs 100

Although the foregoing has been described in some detail by way ofillustration and example for purposes of clarity and understanding, oneof skill in the art will appreciate that certain changes andmodifications can be practiced within the scope of the appended claims.In addition, each reference provided herein is incorporated by referencein its entirety to the same extent as if each reference was individuallyincorporated by reference.

What is claimed is:
 1. A composition comprising about 10% efinaconazoleby weight, water, C12-15 alkyl lactate, diisopropyl adipate,cyclomethicone, ethanol, butylated hydroxytoluene (BHT), a salt ofethylenediaminetetraacetic acid (EDTA), and citric acid, wherein: theamount of BHT ranges from about 0.01% (w/w) to about 2% (w/w), theamount of the salt of EDTA ranges from about 0.0001% (w/w) to about 1.5%(w/w), the amount of citric acid ranges from about 0.05% (w/w) to about0.25% (w/w), and the composition is formulated as a solution.
 2. Thecomposition of claim 1, wherein the amount of the salt of EDTA rangesfrom about 0.0001% (w/w) to about 0.0005% (w/w).
 3. The composition ofclaim 2, wherein the amount of the salt of EDTA is about 0.00025% (w/w)and the amount of BHT is about 0.1% (w/w).
 4. The composition of claim1, wherein the amount of citric acid ranges from about 0.075% (w/w) toabout 0.15% (w/w).
 5. The composition of claim 1, wherein: the amount ofethanol ranges from about 50% to about 70% (w/w), the amount ofcyclomethicone ranges from about 10% to about 15% (w/w), the amount ofdiisopropyl adipate ranges from about 8% to about 15% (w/w), and theamount of C12-15 alkyl lactate ranges from about 8% to about 15% (w/w).6. The composition of claim 5, wherein the amount of the salt of EDTAranges from about 0.0001% (w/w) to about 0.0005% (w/w).
 7. Thecomposition of claim 6, wherein the amount of the salt of EDTA is about0.00025% (w/w) and the amount of BHT is about 0.1% (w/w).
 8. Thecomposition of claim 5, wherein the amount of citric acid ranges fromabout 0.075% (w/w) to about 0.15% (w/w).
 9. The composition of claim 1,wherein: the amount of the salt of EDTA is about 0.00025% (w/w), theamount of BHT is about 0.1% (w/w), the amount of citric acid ranges fromabout 0.075% (w/w) to about 0.15% (w/w), the amount of ethanol rangesfrom about 50% to about 70% (w/w), the amount of cyclomethicone rangesfrom about 10% to about 15% (w/w), the amount of diisopropyl adipateranges from about 8% to about 15% (w/w), and the amount of C12-15 alkyllactate ranges from about 8% to about 15% (w/w).
 10. A method oftreating a fungal infection comprising administering a therapeuticallyeffective amount of a formulation according to claim 1 to a patient inneed of such treatment.
 11. A method of treating a fungal infectioncomprising administering a therapeutically effective amount of aformulation according to claim 9 to a patient in need of such treatment.12. The method of claim 11, wherein the fungal infection isonychomycosis.
 13. The method of claim 12, wherein the administeringcomprises applying the formulation to a nail of the subject at leastthree times a week for a period ranging from about one week to about 12weeks.
 14. The method of claim 13, wherein the formulation is appliedonce daily.
 15. The method of claim 13, wherein the formulation isapplied twice daily.